The Decline and Fall of Cytotoxic Chemotherapy

Keith Stewart, MBChB, MBA
Carlson and Nelson Endowed Director, Center for Individualized Medicine, and Vasek and Anna Maria Polak Professor of Cancer Research, Mayo Clinic in Scottsdale, Arizona

Here, Dr. Stewart gives his take on whether cytotoxic chemotherapy should be declared a thing of the past.

As ward rounds ended last Saturday, a slow-brew blend of my own clinical experience and what I have seen as reproducibly disappointing outcomes coalesced in my strong desire to speed the delivery of cytotoxic chemotherapy to the waste heap of failed medical experiments.

But, let’s start with some background: My telomeres are shortening, I need reading glasses overnight (which I usually can’t find), I yell at the television randomly, and 11 p.m. is a late night for me. Most troublesome of all, I have high-definition flashbacks to my internship on the leukemia ward, filling syringes with adriamycin, methotrexate, and mitoxantrone without wearing gloves or plastic safety glasses. This may explain the failing eyesight, the ear hair, and the strange brown spots on the back of my hands. In what I could probably patent as an early indicator of cortical loss, what I remember most about those drugs was their scary primary-color hues of red, yellow, and blue.

Now fast-forward 30 years to last Saturday and picture me driving to work after a late night arguing with the television, carefully dodging police radar, and inevitably spilling coffee.

Then picture me again when I discover that I am alone at the clinic – not a fellow, intern, resident, or medical student in sight. I conjure up images of how these trainees are spending their time while I’m at work – pretty young things pushing baby strollers while their partners squeeze fresh oranges, or unwinding in the eucalyptus steam room after their Saturday morning yoga class.

“They wouldn’t get away with this in Boston or New York,” I think to myself. “No sir. The trainees there probably come in for rounds at 6 a.m., they’re not allowed to eat until noon, and they don’t dare set foot outside the ward until the last discharge orders have been wrestled from a computer running on 80s-era bandwidth.”

I conclude that I am jealous and another day repairing the havoc wrought by cytotoxic treatment ensues. A day +4 nausea,  a day +19 39oC,  a day +27 without count recovery needs a marrow on Monday. I would love to send some patients home, but defer that decision until someone who can work the computer shows up. Failingly that, so, I lobby any mobile patient to go outside for sunshine. However, this is America, and a lawyer has banned fresh air or trips home to collect a toothbrush; “patio privileges” are dispensed with the enthusiasm of a bank loan.

Nevertheless, by noon, the coffee stains have faded, I am invigorated by patient interaction, the nurse practitioners have bailed me out again, and I am satisfied to have helped in a small way.

Then, spontaneously in the elevator, quarks collide, atoms fuse, long suppressed synapses fire, and I announce to a surprised intern (who must have wandered in to work by accident), “Cytotoxic chemotherapy is a failed 50-year experiment in medical history.”

Before they can respond, I reflect that hematology is the cytotoxic success story – just look at the high-water marks of Hodgkin lymphoma, childhood acute lymphocytic leukemia, and diffuse large B-cell lymphoma – but also impart (with some salty language) that so many other patients flail through months of awfulness.

I wrap up my soliloquy by theorizing that, like blood-letting, radical mastectomy, tonsillectomy, and wisdom teeth extraction, cytotoxic chemotherapy also will soon be equally hard to justify to those who come after us.

En route home, I imagine colleagues around the world re-enacting my weekend rounds with much the same cast, and speculate that, with a collective willingness, we could soon push aside the veil of modest success to embrace the rallying cry of “ABC” or “anything but chemotherapy.” The required tools are being molded, iterated, and sharpened: more potent and specific kinase inhibitors, immune modulators, engineered cellular products, and viral oncolytics, all guided by genomics. There are also protein degraders, metabolism modifiers, and things we haven’t even yet imagined.

It is time to declare the beginning of the end – not to cancer, but to failed cancer treatments – and to band together around a better way: to reward – not discourage – physician engagement in clinical investigation and to make trial participation a badge of honor for patients; to make it socially dishonorable to choose the easier path of palliative cytotoxic therapies when a novel approach is there to be tested; to send grant dollars to places where new approaches are embraced and urgency is palpable; to actively discourage timid and incremental change; to not be limited by the economic doomsayers; to focus on answers first and to remember that patent protections are short in the long arc of human history; to do all of this with a ceaseless velocity.

Maybe then, on Saturdays, my drive to the hospital will be energized, my step more purposeful, and my memories of administering noxious and often ineffective poisons consigned to my long-term hippocampal memory where they belong. Maybe the trainees will show up – even when they don’t have to – just because they are inspired. Maybe I’ll be able to find my reading glasses.

The content of the Editor’s Corner is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated.

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